The invention relates to non-invasive transnasal drug multi-delivery into an organism using electrotransport or phonoforesis as well as an administration device that prevents irritation of the tissue in and around the nasal cavity.
A variety of approaches currently exist for delivering biologically active agents to the central nervous system (CNS). These include, among possible others, oral administration, intravenous-, intramuscular- and transcutaneous administration. All of the above drug delivery approaches tend to be systemic, meaning that the drug is delivered into the systemic circulation, being carried to all internal organs and tissues and it has to pass through the blood-brain barrier (BBB) in order to access the CNS. Obviously, all other organs are being exposed to the drug, which may lead to a high incidence of side effects, particularly with those medications toxic to certain organs (e.g. nephrotoxic, hepatotoxic etc.). Most importantly, the therapeutic efficacy of numerous highly effective biologically active agents (e.g. large compounds, hydrophilic and charged substances such as peptides) is restricted, because they cannot or poorly penetrate the BBB, resulting in sub-therapeutic brain levels of these substances. High systemic levels have to be generated, in order to create therapeutic concentrations in the CNS, but for many therapeutic substances, even this strategy is not always effective. Therefore, there is a large interest in development of alternative drug delivery methods for the central nervous system.
In humans and primates, the olfactory epithelium or olfactory mucosa is located at the top of the nasal cavity between the central nasal septum and the lateral wall of each main nasal passage. This region of the nasal cavity, which is free of airflow, lies just under the cribriform plate of the ethmoid bone that separates the nasal and cranial cavities. In humans, the olfactory epithelium covers an area in the nose of approximately 2 cm2 to 10 cm2. The total olfactory surface area varies with age and between individuals. The olfactory area can be reached through the naris following the nasal septum in a superior and posterior direction. The middle turbinate, which closely opposes the septum usually prevents access to this region, fortunately, this obstruction is not surmountable.
In the last decade, a number of articles were published that describe the delivery of drugs into the brain by administering the drug in the olfactory area, and also a small number of patents have been issued that describe the use of the olfactory pathways to the brain as possible alternative drug delivery methods. For example, U.S. Pat. No. 5,624,898 issued by Frey W. H.; WO 033813A1 issued by Frey W. H.; WO 09901229A1 issued by Gizurarson S. and WO 044350A1 issued by Cevc et al. These patents all relate to the passive delivery of substances to the brain using the olfactory pathways. The agent is administered in the olfactory region, and transport of the agent is based on passive diffusion through the olfactory epithelium. However, compounds that are hydrophilic, charged and/or larger than 300 Dalton may be not delivered in therapeutic effective amounts by the methods described in the cited references. These compounds, but also all other compounds, may be delivered more rapidly and more effectively by means of a physical enhancement technique such as electrotransport as for instance has been described in U.S. Pat. Nos. 7,033,598 and 7,200,432 issued by Lerner E. N., and/or phonophoresis (sonophoresis). The use of an enhancement technique such as electrotransport has the additional advantage that it can provide a dose- and rate-controlled delivery of the biologically active agent and the dose can be pre-programmed according to individual needs.
For chronic diseases, drugs/medications may be administered everyday, sometimes times two or three times a day, for many months and years. For example, these chronic conditions include Alzheimer's disease, Parkinson's and other diseases that have to be treated for many years.
It is known that drug delivery in the skin using iontophoresis irritates the skin so another drug may be needed to treat the irritation. Using intranasal drug delivery can also irritate the tissue of the nasal cavity, and thus it has been difficult to transnasally deliver medication while preserving patient comfort.